Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/60—Three or more oxygen or sulfur atoms
  • C07D239/62—Barbituric acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/06—Phosphorus compounds without P—C bonds
  • C07F9/22—Amides of acids of phosphorus
  • C07F9/24—Esteramides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
  • C07F9/6509—Six-membered rings
  • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3

Definitions

• This invention relates to a process for preparing pyrimidinetrione derivatives. It also relates to novel N-dihydroxyphosphoryl pyrimidinetrione derivatives which may be useful as water-soluble prodrugs of certain pyrimidinetrione compounds.
• febarbamate 1-(3-n-butoxy-2-carbamoyloxypropyl)-5-ethyl-5-phenyl-(1H,3H,5H) pyrimidine-2,4,6-trione known as and hereinafter called febarbamate has previously been prepared and described--see for example Helvetica Chimica Acta, XLIV, pp. 105-113, 1960, and British Patent Specifications No. 1 581 834 and No. 2 137 999. These publications also describe related compounds and their preparation.
• the method of preparation has always involved the alkylation of a 5,5-disubstituted pyrimidinetrione by forming the sodium salt of the appropriate malonyl urea derivative and reacting this with an alkylating agent corresponding to the compound it is desired to prepare--generally a 1-halo-2-carbamoyloxy-3-alkoxy propane, and usually the chloro-compound.
• Such a process always provides a mixture of unchanged starting material, the N'-monosubstituted 5,5-disubstituted pyrimidinetrione derivative and the N,N'-disubstituted 5,5-disubstituted pyrimidinetrione derivative.
• R 1 and R 2 which may be the same or different, represent aliphatic, araliphatic or aryl groups, and R represents a group --CH 2 CH(OCONH 2 )--C 2 OX in which X is a C 1-5 alkyl group, which comprises reacting a compound of formula (II) ##STR2## wherein R 1 and R 2 and X are as defined above with a dihalophosphinyl or halosulphonyl isocyanate to obtain a compound of formula (III) ##STR3## wherein R 1 and R 2 and X are as defined above and Z is a group of formula --SO 2 Y or --POY 2 wherein Y is a halogen atom, followed by hydrolysis of the compound of formula (III).
• intermediate compounds of formula (III) are believed novel, comprise a further feature of the invention, and may either be isolated, or may be hydrolysed in situ to provide compounds of formula (I) as defined above.
• Y is a chlorine atom.
• the reaction of the compounds of the formula (II) with a dihalophosphinyl or a halosulphonyl isocyanate may be carried out in solution, preferably in an anhydrous organic solvent, desirably an aromatic hydrocarbon such as toluene or a halogenated hydrocarbon such as methylene chloride, using substantially equimolar amounts of the reactants at a temperature between -10° to 50°.
• anhydrous organic solvent desirably an aromatic hydrocarbon such as toluene or a halogenated hydrocarbon such as methylene chloride, using substantially equimolar amounts of the reactants at a temperature between -10° to 50°.
• the complete reaction generally requires 1 to 5 hours, typically 1 hour at room temperature.
• the hydrolysis reaction may conveniently be conducted in a mixture of solvents, preferably an organic hydrocarbon solvent, such as toluene or cyclohexane, and water at pH 4 to 6 and at a temperature in the range 40° C. to 110° C., typically at about 70° C.
• solvents preferably an organic hydrocarbon solvent, such as toluene or cyclohexane
• the reaction time varies strongly depending on the conditions used from 1 to 24 hours, but typically about 6 hours at a pH of about 5.5 and at about 70° C. are required.
• the compounds according to the invention may be formulated for administration as pro-drugs in any convenient way, but with particular advantage for injection and controlled-release compositions.
• the active ingredient may be presented in a powder form in ampoules or in other sterile containers and dissolved in a suitable sterile solvent shortly before use.
• compositions in the form of partially soluble salts or absorbed on resins or in any other form known in the art.
• Suitable pharmaceutically acceptable diluents or excipients may be selected with ease by anyone skilled in the art.
• the compounds of the formula (II) have been described as being prepared (Helvetica Chimica Acta, XLIV, pp. 105-113, 1960) by reaction of 5,5-disubstituted malonyl urea sodium salt with 1-chloro--2-hydroxy-3-alkoxy propane.
• the procedure described is highly laborious and quite impractical on a commercial scale in view of the heating times involved and the need to distil several times under reduced pressure to obtain a product of suitable purity. It will be realised that the preparation described in this reference provides a mixture of products, and the yields obtained were on the low side.
• a process for the preparation of the compounds of formula (II) as defined above which comprises reacting a compound of formula (V) ##STR5## wherein R 1 and R 2 are as defined above with a compound of formula (VI) or (VIa) ##STR6## wherein X is as defined above and Hal is a halogen atom in the presence of approximately 0.01 to 0.1 molar equivalents of an organic base when a compound of formula (VI) is used, or approximately 1.0 molar equivalents of an organic base when a compound of formula (VIa) is used.
• the base used will most desirably be selected so as to possess a pkB higher than about 10 in water.
• an organic base that will act also as a solvent for the reaction, or at least assist solubilisation of the reagents, a much smoother reaction in a homogeneous medium can be carried out which has significant handling advantages on a commercial plant scale.
• bases are aliphatic, araliphatic or aromatic amines optionally substituted by hydroxyl or further amino groups, the trialkylamines, and particularly triethylamine being most preferred.
• Reaction will desirably be carried out in a protic organic solvent such as a lower alkanol, e.g. ethanol or n-butanol, or an aprotic solvent such as an amide, e.g. dimethylformamide or dimethylacetamide, or those described above which may also comprise a suitable base, or in any suitable mixture thereof.
• a protic organic solvent such as a lower alkanol, e.g. ethanol or n-butanol
• an aprotic solvent such as an amide, e.g. dimethylformamide or dimethylacetamide, or those described above which may also comprise a suitable base, or in any suitable mixture thereof.
• the temperature employed in this reaction will generally be in the range 20°-150° C., preferably 70° C., and a reaction time of from 2-48 hours is required, preferably 6 hours.
• the compounds of formula (II) obtained may be isolated from the reaction mixture by methods described in British Patent Specification No. 1581834.
• the whole process is particularly well suited to a large-scale production of febarbamate (the compound of formula (I) in which R 1 is ethyl, R 2 is phenyl and R is a 3-n-butoxy-2-carbamoyloxypropyl group) and its derivatives using only very classical operations such as extractions, crystallizations, filtrations and evaporations.
• febarbamate the compound of formula (I) in which R 1 is ethyl, R 2 is phenyl and R is a 3-n-butoxy-2-carbamoyloxypropyl group
• the precipitated phenobarbital was filtered off and the filtrate extracted with 5% aqueous sodium carbonate (5 ⁇ 100 ml).
• the organic layer was then extracted with 1M aqueous sodium hydroxide (2 ⁇ 200 ml), the aqueous layers collected, washed with toluene (100 ml) and the pH was adjusted to 3 with sulphuric acid.
• the precipitated product was extracted with toluene (150 ml), the organic layer was separated, dried and evaporated under reduced pressure to give the title compound (40.1 g, 55%); purity by HPLC 99% m.p. 92° C.
• the precipitated phenobarbital was filtered off and filtrate extracted with 5% aqueous sodium carbonate (5 ⁇ 100 ml).
• the organic layer was then extracted with 1M aqueous sodium hydroxide (2 ⁇ 200 ml), the aqueous layers collected, washed with toluene (100 ml) and the pH was adjusted to 3 with sulphuric acid.
• the precipitated product was extracted with toluene (150 ml), the organic layer was separated, dried and evaporated under reduced pressure to give the title compound (38.5 g, 53%); purity by HPLC 96.5% .
• reaction mixture was stirred for 1 hour at room temperature and then ice-cold water (100 ml) was added. After a vigorous reaction had ceased the pH of the solution was adjusted to 5 using a solution of sodium hydroxide.
• the toluene phase was then extracted with 1M aqueous sodium hydroxide (2 ⁇ 100 ml), the aqueous layers separated, washed with toluene (100 ml) and the pH was adjusted to 3 with sulphuric acid.
• the precipitated oily product was extracted with toluene (100 ml), and the organic layer was separated, washed with water, dried and evaporated to yield the title compound (16.3 g; 51.6%); purity by HPLC 96.5%.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Molecular Biology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Biochemistry (AREA)
• General Health & Medical Sciences (AREA)
• Health & Medical Sciences (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Compositions Of Macromolecular Compounds (AREA)
• Dental Preparations (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Preparation Of Compounds By Using Micro-Organisms (AREA)

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• 1990
  • 1990-02-08 GB GB909002890A patent/GB9002890D0/en active Pending
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• 1991
  • 1991-02-05 DE DE69104920T patent/DE69104920T2/de not_active Expired - Fee Related
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  • 1991-02-05 KR KR1019910701274A patent/KR920701173A/ko not_active Ceased
  • 1991-02-05 AT AT91903577T patent/ATE113589T1/de not_active IP Right Cessation
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• 1992
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• 1993
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• 1995
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